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Abbas Shirinifard, James A. Glazier; The Role of VEGF-A Overexpression and Bruch’s Membrane Defects in Choroidal Neovascularization: A Computer Simulation Study. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2988.
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© ARVO (1962-2015); The Authors (2016-present)
Choroidal neovascularization (CNV) of the macular area of the retina is the major cause of severe vision loss in patients with age-related macular degeneration (AMD). The factors determining both CNV initiation and progression are poorly understood. Controlled experiments on choroidal neovascularization (CNV) are difficult because no animal model exhibits the full range of age-related CNV pathologies and in vitro experiments fail to reproduce CNV or to form drusen. We have developed computational models which allow us to control the identity and degree of activity of specific biological mechanisms without confounding crosstalk or quantitative uncertainties to evaluate their contribution to the initiation and progression of CNV.
Our 3D multi-scale multi-cell model includes key retinal components, mechanisms including cell-cell, cell-extracellular matrix (ECM) and ECM-ECM adhesion, and major angiogenesis-related processes, including BrM breakdown, hypoxic signaling via upregulation of vascular endothelial growth factor (VEGF), and VEGF and oxygen transport.
We used our model to simulate the effects of VEGF overexpression in the RPE and the effects of defects in BrM on CNV initiation and progression. Our key findings are: 1) Sub-RPE CNV only forms when attachment of the basement membrane of the RPE to BrM fails. 2) VEGF overexpression increases risk of initiating sub-retinal CNV, but it does not promote sub-RPE CNV. 3) Holes in BrM larger than about 40 μm, disrupt RPE integrity, leading to sub-retinal CNV, but not sub-RPE CNV.
Our findings suggest that 1) age-related changes, like lipid accumulation in BrM which interferes with adhesion of the basement membrane of the RPE to BrM, may be key factors in initiation of sub-RPE CNV in AMD, 2) VEGF overexpression and severe BrM defects may promote progression of sub-RPE CNV to sub-retinal CNV in AMD.
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